Addiction to illicit and prescription opioid narcotic drugs (heroin, morphine, codeine, oxycodone and related agents) is a significant public health issue. Each month in the US, 4.9% of persons aged 12 or older (>11 million) use prescription pain relievers for non-medical purposes. Young adults (age 18 to 25) are particularly hard hit by this problem, and they have the highest rate of abuse of prescription pain relievers (Results from the 2006 National Survey on Drug Use and Health: National Findings. Substance Abuse and Mental Health Services Administration, Department of Health and Human Services, 2006). Opioid addiction has adverse consequences for personal health and society (Birnbaum, H. G., et al., Clin J Pain, 2006. 22(8): p. 667-676; Gruber, S. A. et al. Neuropsychol Rev, 2007. 17(3): p. 299-315; Manchikanti, L., Pain Physician, 2006. 9(4): p. 287-321). As many as 90% of patients in chronic pain management settings receive opioid pain relievers, and the prevalence of drug abuse is 9-41% among these patients (Manchikanti, L., supra). Anxiety, increased pain sensitivity, poor concentration, tachycardia and flu-like symptoms develop during opioid withdrawal, a syndrome reflecting physical dependence on these drugs (Handelsman, L., et al., Am J Drug Alcohol Abuse, 1987. 13(3): p. 293-308). The severity of the dependence and resulting withdrawal symptoms is a major contributor to the addictive potential of opioid narcotics. Current strategies for treatment of opioid withdrawal are suboptimal; they rely on the administration of controlled substances (methadone and buprenorphine), or medications with significant hemodynamic side effects (clonidine).
The misuse of and addiction to opioid drugs can be initiated after exposure to prescribed medications in a clinic (or involve a medical source). Thus, clinical interventions that reduce the risk for misuse and addiction could have a substantial impact on this public health problem. A prevention model has not been previously pursued in which physicians co-prescribe medications in combination with addicting agents to reduce the risk of subsequent misuse, dependence, or addiction. This is due to most of the addicting agents (cocaine, heroin, marijuana) were illicit drugs obtained from non medical sources. However, opioid narcotics are commonly obtained from legitimate medical sources. Therefore, this raises the probability that co-administration a medication that alleviates the iatrogenic influences that contribute to and sustain the misuse and abuse of prescription opiate medications would be of substantial benefit.
Since it could lead to new approaches for prevention or treatment of addiction, identification of novel genetic factors affecting dependence on opioids is also of great public health significance. Susceptibility to opioid addiction is heritable in humans (Kendler, K. S., et al. Am J Psychiatry, 2003. 160(4): p. 687-695). One dimension of addiction is physical dependence which can be modeled in rodents. The jumping behavior displayed by morphine-dependent mice after administration of naloxone, a potent opioid receptor antagonist, is a commonly used measure of physical dependence. Naloxone-precipitated jumping is a highly heritable trait amongst inbred mouse strains (Kest, B., et al., Mamm Genome, 2004. 15(8): p. 610-617), and the inter-strain differences are largely independent of differences in the method of drug administration or the duration of treatment (Kest, B., et al. Pharmacol Biochem Behav 2002. 73(4): p. 821-828; Liang, D. Y., et al. Pain, 2006. 121(3): p. 232-240). Furthermore, naloxone-precipitated withdrawal has been used to quantify opioid dependence in human volunteers (Bickel, W. K., et al., NIDA Res Monogr, 1986. 67: p. 349-54). Despite these facts, no specific genes linked to physical dependence have been identified.
Computational genetic mapping (Wang, J., et al., Trends Genet. 2005. 21(9): p. 526-532; Liao, G., et al., Science, 2004. 306(5696): p. 690-695) can be used to identify several genetic factors underlying the variability in morphine-induced alterations in pain sensitivity (hyperalgesia) and responsiveness to analgesic medications in mice (Liang, D. Y., et al., Pharmacogenet Genomics 2006. 16(11): p. 825-835; Liang, D. Y., et al. Anesthesiology, 2006. 104(5): p. 1054-1062; Smith, S. B., et al., Pharmacogenet Genomics, 2008. 18(3): p. 231-241). Haplotype-based computational genetic mapping can be used to identify genes affecting susceptibility to opioid dependence in mice, and a pharmacologic agent targeting the human homologue of the computationally identified murine gene can alleviate the signs and symptoms of withdrawal in humans.